Disease relevance of NCK2

• Grb4 may therefore play a role in the molecular pathogenesis of chronic myelogenous leukemia [1].

High impact information on NCK2

• These cellular responses can be blocked in a dominant-negative fashion by expression of the isolated Grb4 SH2 domain [2].
• Here we show that the SH2/SH3 domain adaptor protein Grb4 binds to the cytoplasmic domain of B ephrins in a phosphotyrosine-dependent manner [2].
• Accordingly, gamma-secretase inhibitors prevented the EphB-induced sprouting of endothelial cells and the recruitment of Grb4 to ephrinB [3].
• These data provide novel structural insight into LIM domain-mediated protein-protein recognition and demonstrate that the PINCH-Nck2 interaction is an important component of the focal adhesion assembly during integrin signaling [4].
• Grb4 bound to Bcr-Abl in a variety of systems, both in vitro and in vivo, and is an excellent substrate of the Bcr-Abl tyrosine kinase [1].

Biological context of NCK2

• Our results suggest a novel role for Grb4 in the inhibition of promitogenic enhancer elements such as 12-O-tetradecanoylphorbol-13-acetate-responsive element and SRE [5].
• The Nck-2 SH2 domain-mediated interaction with FAK is dependent on phosphorylation of Tyr397, a site that is involved in the regulation of cell motility [6].
• Nck-2 interacts with focal adhesion kinase and modulates cell motility [6].
• Two additional, albeit much weaker, Nck-2 SH3 binding sites are located to DOCK180 residues 1793-1810 and 1835-1852 respectively [7].
• We have identified in a yeast two-hybrid screen DOCK180, a signaling protein implicated in the regulation of membrane ruffling and migration, as a binding protein for Nck-2 [7].

Anatomical context of NCK2

• Finally, we provide evidence indicating that a fraction of the Nck-2 and/or Nck-1 proteins are associated with the cytoskeleton [8].
• Although neither protein was transforming on its own, both Nck and Grb4 cooperated with v-Abl to transform NIH 3T3 cells and influenced the morphology and anchorage-dependent growth of wild type Ras-transformed cells [9].
• In the present study, we report the isolation of Xenopus Grb4 (growth-factor-receptor-bound protein 4), an ephrinB1-interacting protein, and we show that when expressed in Xenopus oocytes, ephrinB1 interacts with Grb4 in the presence of an activated FGFR1 [10].

Co-localisations of NCK2

• A fraction of Nck-2 co-localizes with FAK at cell periphery in spreading cells [6].

Other interactions of NCK2

• Additionally, biochemical studies indicate that ILK, through the interaction with PINCH, is capable of forming a ternary complex with Nck-2, an SH2/SH3-containing adapter protein implicated in growth factor receptor kinase and small GTPase signaling pathways [11].
• The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains [12].
• Furthermore, we show that Nck-2 is capable of recognizing several key components of growth factor receptor kinase-signaling pathways including EGF receptors, PDGF receptor-beta, and IRS-1 [8].
• Additionally, we have detected a stable association between Nck-2 and IRS-1 that was mediated primarily via the second and third SH3 domain of Nck-2 [8].
• Suppression of Grb2 or Nck2 results in loss of localization of N-WASP at the activation site and reduced actin polymerization [13].

Analytical, diagnostic and therapeutic context of NCK2

• Indeed, cell fractionation and fluorescence microscopy studies revealed that the stronger inhibitory potential of the Grb4 SH2 mutant occurred in conjunction with increased nuclear localization of this mutant [5].
• (3) Several high-affinity bindings were identified for hNck2 SH3 domains by isothermal titration calorimetry [14].

References